Project Summary/Abstract There is a significant comorbidity of alcoholism with other psychiatric conditions. One of the most prominent of these comorbid disorders is major depression, where alcoholics are at approximately four-fold greater risk of experiencing major depression relative to non-alcoholics. In this proposal we will examine the mechanisms that mediate this comorbidity by inducing co- expressed depressive-like behavior and escalated alcohol consumption using preclinical rodent models. Specifically, we will use exposure to chronic social defeat stress to induce these behavioral phenotypes. We will examine the hypothesis that the neurokinin-1 receptor (NK1R) mediates the influence of social defeat stress exposure on subsequent alcohol intake and depressive-like behavior. We have previously shown that this receptor influences stress- induced alcohol seeking in rodents, and as such, this receptor is an ideal target to influence social stress-induced alcohol intake in this mouse model. In specific regard to defeat stress, we have found that the NK1R is upregulated in animals that are sensitive to this stressor. However, one drawback of the defeat stress model is that it can only be used in male mice due to sex differences in territorial aggression. This is a significant issue for the concepts studied here because clinical depression is far more common in females than in males. Thus, we will use a different stressor, immune stimulation by the bacterial cell wall component lipopolysaccharide (LPS), to study these behaviors in both sexes. LPS is known to increase alcohol intake and depressive-like behavior in both male and female mice, and our preliminary data indicates that some effects of LPS are dependent upon the NK1R. Together, these aspects make LPS injection a relevant model for examining alcoholism and depression comorbidity in both sexes. The role of the NK1R in LPS effects suggests that a similar neurocircuitry may regulates the response to both defeat stress and LPS-induced behavioral alterations. The results of these studies will significantly contribute to our understanding of the factors that influence comorbid alcoholism and depression, and will identify novel candidate targets for medications development.